ABSTRACT Effective control of chronic pain is a top priority in the United States, as approximately 10% of adults have severe chronic pain ? most of which is chronic lower back pain (CLBP). However, despite the advances in neuroscience over the past 20 years, we still largely treat chronic pain with opiate narcotics, much as was done in the Civil War. In addition to their high abuse liability and dependence potential (1), only 30?40% of chronic pain patients declare they receive satisfactory (>50%) relief from their pain through pharmacological treatment. Consequently there is a critical need for new, treatments that can treat pain and reduce reliance on opiates in individuals with chronic pain. The goal of this R21 proposal is to evaluate 2 novel non-invasive brain stimulation strategies to mitigate pain and the brain's response to pain in CLBP patients currently taking chronic opiates. Transcranial Magnetic Stimulation (TMS), can induce long term potentiation (LTP-like) and long term depression (LTD-like) effects on brain activity in a frequency dependent manner. Our group has previously demonstrated that LTP-like TMS to the dorsolateral prefrontal cortex (DLPFC, a node in the Executive Control Network (ECN)) can decrease perceived pain and corresponding BOLD signal in the ?Pain Network? (Strategy 1, Aim 1). An alternative strategy is to apply LTD-like stimulation to the medial prefrontal cortex (MPFC, a node in the Default Mode Network (DMN); Strategy 2, Aim 2). The proposed study will be the first to employ a randomized, double-blind, sham-controlled design to parametrically evaluate the longitudinal effects of 10 days of rTMS to the DLPFC (Aim 1) or the MPFC (Aim 2) on self-reported pain and the brain's response to pain. This will be done in a cohort of patients with chronic lower back pain that have been using prescription opiates for 3 or more months without adequate pain relief. Patients will be recruited from the comprehensive pain management clinic at MUSC (directed by Dr. Borckardt, Co-I) and MUSC General Medicine clinics. Quantitative Pain testing and Brain reactivity to pain will be measured immediately before and after 10 days of TMS as well as a 1 and 2 month follow-up (to evaluate durability).